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2014-05-05

Novartis International AG: Novartis drug Signifor® LAR shows superior efficacy in acromegaly patients not controlled on first generation somatostatin analogue

Novartis International AG / Novartis drug Signifor® LAR shows superior
efficacy in acromegaly patients notcontrolled on first generation
somatostatin analogues . Processed and transmitted by NASDAQ OMX Corporate
Solutions.The issuer is solely responsible for the content of this
announcement.
* Acromegaly, an endocrine disorder resulting from elevated growth hormone
(GH) and insulin-like growth factor-1 (IGF-1) levels, is associated with
high mortality[1,2]
* Phase III data show patients on pasireotide LAR achieved greater
biochemical control, as measured by both GH and IGF-1 levels, versus
control group[3]
* These data, supported by a previously published Phase III study, are the
basis for worldwide regulatory filings for pasireotide LAR in the treatment
of acromegaly

Basel, May 5, 2014
-
Novartis today presented results from a pivotal Phase III trial of
investigational therapy Signifor®LAR (pasireotide LAR; SOM230) in patients
with acromegaly for whom current standard of care provides inadequate disease
control. The study findings showed that patients taking pasireotide
long-acting release (LAR) achieved greater disease control when compared to
continued treatment with the standard somatostatin analogue therapies,
octreotide LAR or lanreotide Autogel*. These data were presented at the
16thEuropean Congress of Endocrinology[3].

Acromegaly is caused by a benign (non-cancerous) tumor within the pituitary
gland that secretes excess growth hormone (GH), leading to elevated levels of
insulin-like growth factor-1 (IGF-1)[1]. This combined effect of elevated GH
and IGF-1 levels causes the enlargement of body parts, including the hands,
feet and facial features, along with serious morbidities such as
cardiovascular, metabolic and respiratory diseases[1,4]. If exposed to
long-term elevated levels of GH and IGF-1, acromegaly patients face a two- to
three-fold increased risk of death[2,5]. Biochemical control of the disease,
as measured by both GH and IGF-1 levels, is the primary goal of treatment.
Other disease management objectives include tumor shrinkage and improvement
in clinical signs and symptoms[1].

"Historically, we have evaluated somatostatin analogues for the treatment of
acromegaly by the decrease in either growth hormone or insulin-like growth
factor levels. With more sensitive assays and more stringent evaluation
criteria, a recent meta-analysis indicates that up to 45% of patients can
have either GH or IGF-I still elevated," said Dr. Monica Gadelha, professor,
Federal University of Rio de Janeiro and study author. "As the health risks
associated with acromegaly may persist until both GH and IGF-1 levels are
normalized, this study further supports the importance of monitoring for and
achieving full biochemical control."

This study evaluated pasireotide LAR 40 mg and 60 mg against continued therapy
with octreotide LAR or lanreotide Autogel in patients who did not achieve GH
and IGF-1 biochemical control despite receiving the maximum approved doses of
these currently available somatostatin analogues (SSAs). In the trial,
significantly more patients achieved biochemical control with each dose of
pasireotide LAR compared to the octreotide LAR and lanreotide Autogel control
arm. Specifically, 15.4% and 20.0% of those with inadequately controlled
acromegaly taking pasireotide LAR 40 mg and 60 mg, respectively (95%
confidence interval [CI], 7.6-26.5; P=0.0006; 95% CI, 11.1-31.8; P<0.0001),
achieved biochemical control versus 0% achieving biochemical control on
continued treatment with octreotide LAR or lanreotide Autogel (95% CI,
0-5.3). The incidence and severity of adverse events (AEs) was similar across
all treatment groups, except for a higher frequency and degree of
hyperglycemia in the pasireotide LAR arm[3].

"These results strengthen our understanding of this rare endocrine disorder
and suggest pasireotide LAR may offer benefit for acromegaly patients whose
disease is not fully controlled on their current therapy," said Alessandro
Riva, president, Novartis Oncology ad interim and Global Head, Oncology
Development and Medical Affairs. "As part of our long-standing commitment to
transforming the care of rare pituitary diseases, we are working to bring
this potentially meaningful solution to the acromegaly community."

Worldwide regulatory filings for pasireotide LAR in acromegaly are currently
underway based on these results and separate previously published robust
Phase III data.

About the study
The multicenter Phase III study was a randomized, double-blind trial examining
pasireotide LAR 40 mg or pasireotide LAR 60 mg versus continued open-label
treatment with octreotide LAR 30 mg or lanreotide Autogel 120 mg (the control
group) for 24 weeks. The trial included 198 patients with inadequately
controlled acromegaly on maximum approved doses of octreotide LAR or
lanreotide Autogel for at least 6 months, regardless of prior surgical
status. The primary endpoint of this study was the proportion of patients
achieving biochemical control as measured by the mean GH levels of<2.5Mu g/L
and normalized IGF-1 at 24 weeks[3].

The key secondary endpoint was the percentage of patients achieving normalized
IGF-1; other secondary endpoints included the percentage of patients
achieving normalized GH levels, tumor reduction and safety. Notably, in this
study, IGF-1 normalization was achieved by 24.6% and 26.2% of patients taking
pasireotide LAR 40 mg and 60 mg, respectively (95% CI, 14.8-36.9; P<0.001;
95% CI, 16.0-38.5; P<0.001) and was not achieved by any patients in the
control arm (95% CI, 0-5.3). Additionally, 35.4% and 43.1% of patients in the
pasireotide LAR 40 mg and 60 mg arms, respectively (95% CI, 23.9-48.2; 95%
CI, 30.8-56.0) had mean GH levels of<2.5Mu g/L compared to 13.2% in the
control arm (95% CI, 6.2-23.6)[3].

Tumor size was also evaluated and the study found a greater proportion of
patients receiving pasireotide LAR 40 mg and 60 mg achieved a greater than
25% decrease compared with those receiving octreotide LAR and lanreotide
Autogel (18.5% [95% CI, 9.9-30.0] and 10.8% [95% CI, 4.4-20.9]versus 1.5%
[95% CI, 0-7.9], respectively)[3].

The most common AEs associated with pasireotide LAR 40 mg, 60 mg and the
control arm were hyperglycemia (33.3%, 30.6% and 13.6%), diabetes mellitus
(20.6%, 25.8% and 7.6%) and diarrhea (15.9%, 19.4% and 4.5%),
respectively[3].

About acromegaly
Worldwide, the estimated prevalence of acromegaly is between 115 and 295
people per million and the estimated incidence is three to four people per
million[6,7]. Acromegaly most commonly presents in middle-aged men and women.
This debilitating disease can be difficult to detect because it can develop
gradually and/or individual symptoms may be mistaken for another medical
condition[1]. In fact, the average delay from disease onset to diagnosis has
been estimated to be 6 to 10 years[8]. Acromegaly is also associated with
serious health risks including heart disease, hypertension, diabetes,
arthritis and an increased risk of colon cancer[1]. Heart disease is
responsible for approximately 60% of deaths among people with acromegaly[9].

About pasireotide and pasireotide LAR
Pasireotide is approved as Signifor®in the US for the treatment of adult
patients with Cushing's disease for whom pituitary surgery is not an option
or has not been curative and in the EU for the treatment of adult patients
with Cushing's disease for whom surgery is not an option or for whom surgery
has failed.

For the treatment of Cushing's disease, Signifor has been studied as a
twice-daily subcutaneous (sc) injection and is currently being evaluated as a
long-acting release (LAR), once-monthly intramuscular (IM) injection as part
of a global Phase III program in Cushing's disease and acromegaly. Signifor
is a multireceptor targeting somatostatin analog (SSA) that binds with high
affinity to four of the five somatostatin receptor subtypes (sst 1, 2, 3 and
5). There is no guarantee that Signifor LAR will become commercially
available anywhere in the world for Cushing's disease or any other
indication.

Pasireotide LAR (SOM230) is an investigational multireceptor targeting SSA
that binds with high affinity to four of the five somatostatin receptor
subtypes (sst 1, 2, 3 and 5). As an investigational agent, the safety and
efficacy profile of pasireotide LAR has not been established in acromegaly or
any other indication. The formulation and dosage of pasireotide LAR when used
for studying the acromegaly patient population are different from that of
pasireotide sc in the approved Cushing's disease indication. Pasireotide LAR
is available for patients with acromegaly through carefully controlled and
monitored clinical trials which are designed to better understand the
potential benefits and risks of the compound. For various reasons, including
the uncertainty of clinical trials, there is no guarantee that pasireotide
LAR will become commercially available for acromegaly anywhere in the world.

Information about Novartis clinical trials for pasireotide can be obtained by
healthcare professionals atwww.clinicaltrials.gov.

Important safety information about Signifor (pasireotide) injection
Signifor is contraindicated in patients with hypersensitivity to the active
substances in Signifor or to any of the excipients and in patients with
severe liver impairment.

Alterations in blood glucose levels have been frequently reported in healthy
volunteers and patients treated with Signifor. Glycemic status should be
assessed prior to starting treatment with Signifor. Patients need to be
monitored for hyperglycemia; if hyperglycemia develops, the initiation or
adjustment of antidiabetic treatment is recommended. Dose reduction or
treatment discontinuation should be considered if uncontrolled hyperglycemia
persists. After treatment discontinuation, glycemic monitoring (e.g. FPG or
HbA1c) should be done according to clinical practice.

Monitoring of liver function is recommended prior to starting treatment with
Signifor and after one, two, four, eight and twelve weeks during treatment
and thereafter as clinically indicated. Therapy should be discontinued if the
patient develops jaundice, other clinical signs of significant liver
dysfunctions, sustained AST (aminotransferases) or ALT (alanine
aminotransferase) increase five times the upper limit of normal (ULN) or
greater, or if ALT or AST increase three times ULN with concurrent bilirubin
elevation greater than two times ULN.

Patients with cardiac disease and/or risk factors for bradycardia need to be
closely monitored. Caution is to be exercised in patients who have or may
develop QT prolongation. Hypokalemia or hypomagnesemia must be corrected
prior to initiating therapy and monitored thereafter. Electrocardiography
should be performed prior to the start of Signifor therapy and as clinically
indi...

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